PROJECT SUMMARY While many targeted and hormonal treatment options exist for hormone-positive breast cancer, only standard chemotherapy is available for the treatment of triple-negative breast cancer (TNBC), which tends to be more aggressive, metastatic, more likely to affect younger people, African Americans, Hispanics, and/or those with a BRCA1 gene mutation. Our published data indicate that Estrogen-Related Receptor alpha (ERR?) may have a prognostic value and may serve as a predictor of response to tamoxifen in TNBC. Moreover, our preliminary data show that ERR? regulates the expression of the 40S ribosomal S6 kinase 1 (S6K1), an effector of the mechanistic target of rapamycin (mTOR) signaling pathway. Based on these data we hypothesize that ERR? expression is a driving factor in pathogenesis of TNBC, whose activity is targeted by tamoxifen treatment. Our objective is to understand the molecular relationship between ERR? and S6K1 expression and drug response in TNBC. This proposal is innovative because it focuses on ERR?, which is overexpressed in triple-negative breast cancer, associated with poor prognosis and may drive TNBC progression, and will provide rationale for paradigm- shifting use of tamoxifen and mTOR inhibitors (such as rapamycin) in TNBC. We will determine tamoxifen-induced changes in genomic binding of ERR?, and the effects on metabolic and signaling activity in TNBC cells. We will investigate the changes in S6K1 expression and sensitivity to mTOR inhibitors as a result of ERR? regulation. The data obtained at the completion of the Specific Aims will create a comprehensive network of the gene expression, metabolic and signaling changes induced by ERR? in TNBC, which may affect cellular responses to tamoxifen and mTOR inhibitors. The wealth of the generated knowledge will allow us to establish a long- term research project to identify putative cellular targets to be studied in greater detail with the goal of exploring new avenues in breast cancer research, and develop new interventions and prognostic markers of therapy response. Expanding the use of tamoxifen and rapamycin, both safe and FDA-approved drugs, may clinically benefit millions of women suffering from TNBC, with the potential to reduce disease mortality.